Naloxone, a drug that instantly reverses opioid overdoses, has been skyrocketing in price for years. And Mylan, the company behind the EpiPen, is involved in the naloxone price hikes as well.

Frequently referred to as an "antidote" for opioid overdoses, naloxone has seen drastic price increases in recent years, according to information provided by Truven Health Analytics, a healthcare-analytics company. A popular injectable version of the drug has gone from $0.92 a dose to more than $15 a dose over the last decade. An auto-injector version is up to more than $2,000 a dose.

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What opioids do to your health

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What opioids do to your health

Opioid painkillers capitalize on our body's natural pain-relief system. We all have a series of naturally produced keys ("ligands") and keyholes ("receptors") that fit together to switch on our brain's natural reward system — it's the reason we feel good when we eat a good meal or have sex, for example. But opioids mimic the natural keys in our brain — yes, we all have natural opioids! When they click in, we can feel an overwhelming sense of euphoria.

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Opioid painkillers can have effects similar to heroin and morphine, especially when taken in ways other than prescribed by a doctor.

When prescription painkillers act on our brain's pleasure and reward centers, they can make us feel good. More importantly, though, they can work to reinforce behavior, which in some people can trigger a repeated desire to use.

You'll begin to feel their effects 10 to 90 minutes after use, depending on whether they're taken as directed or used in more dangerous ways.

Some drugmakers design versions of their medications to deter abuse. Extended-release forms of oxycodone, for example, are designed to release slowly when taken as directed. But crushing, snorting, or injecting the drugs can hasten their effects.

It can also be deadly. Between 2000 and 2014, nearly half a million Americans died from overdoses involving opioid painkillers and heroin, a report from the US Centers for Disease Control and Prevention found. The most commonly prescribed painkillers were involved in more overdose deaths than any other type of the drug.

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Your breathing will slow as well.

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Depending on the method used, the effect can last anywhere from four to 12 hours.

For severe pain, doctors typically prescribe opioid painkillers like morphine for a period of four to 12 hours, according to the Mayo Clinic. Because of their risks, it's important to take prescription painkillers only according to your physician's specific instructions.

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Overdosing can stop breathing and cause brain damage, coma, or even death.

A 2014 report from the American Academy of Neurology estimates that more than 100,000 Americans have died from prescribed opioids since the late 1990s. Those at highest risk include people between 35 and 54, the report found, and deaths for this age group have exceeded deaths from firearms and car crashes.

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Combining them with alcohol or other drugs — even when taken according to the directions — can be especially deadly.

Since they slow breathing, combining opioid painkillers with other drugs with similar effects can drastically raise the chances of accidental overdose and death.

Abusing opioid painkillers has been linked with abusing similar drugs, like heroin.

A CDC report found that people who'd abused opioid painkillers were 40 times as likely to abuse heroin compared with people who'd never abused them. The National Institute on Drug Abuse says that close to half of young people surveyed in three recent studies who'd injected heroin said they'd abused prescription painkillers before they started using heroin.

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You may also develop a tolerance for the drugs so that you need more to get the same effect over time.

Tolerance to opioid painkillers happens when the brain cells with opioid receptors — the keyholes where the opioids fit — become less responsive to the opioid stimulation over time. Scientists think that this may play a powerful role in addiction.

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Suddenly stopping the drugs can result in withdrawal symptoms like shakiness, vomiting, and diarrhea.

Taking prescription painkillers for an extended period increases the likelihood that your brain will adapt to them by making less of its own natural opioids. So when you stop taking the drugs, you can feel pretty miserable. For most people, this is uncomfortable but temporary.

But in people who are vulnerable to addiction, it can be dangerous because it can spurn repeated use.

"From a clinical standpoint, opioid withdrawal is one of the most powerful factors driving opioid dependence and addictive behaviors," Yale psychiatrists Thomas Kosten and Tony George write in a 2002 paper in the Journal of Addiction Science & Clinical Practice.

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A report from the US Centers for Disease Control and Prevention in January revealed that drug overdose deaths reached a new high in 2014, totaling 47,055 people. Opioids were involved in 60% of those deaths.

On the market since 1971, naloxone works by blocking opioid drugs from interacting with the brain's receptors, counteracting the drugs' dangerous side effects, like slow respiration, coma, and death, during an overdose. The drug almost instantly pulls an overdose victim back to sobriety and has only minor side effects for opioid users — and almost none if mistakenly administered to patients not suffering an overdose.

The price increases, however, have made affording the drug difficult for community organizations, which provide naloxone for free to drug users, their family members, and other non-medical personnel.

These organizations along with pharmacies, public-health departments, and substance-use treatment facilities prevented more than 26,000 overdoses from 1996 to June 2014 by providing naloxone, according to a survey of 136 such organizations conducted by the Harm Reduction Coalition, a national advocacy group. That number is also likely lower than the actual number of overdoses prevented, according to the survey.

Many see the drug's price hikes as unwarranted and are frustrated with the lack of access.

"We're not talking about a limited commodity. Naloxone is a medicine that is almost as cheap as sterile sodium chloride — salt water," Dan Bigg, the executive director of the Chicago Recovery Alliance, an outreach organization that has been providing naloxone to drug users for nearly 20 years, told Business Insider.

In June, Sens. Claire McCaskill, a Democrat from Missouri, and Susan Collins, a Republican from Maine, sent a letter to the five pharmaceutical companies that produce naloxone — Amphastar, Pfizer, Adapt, Kaléo, and Mylan — asking for an explanation of the recent price changes.

"At the same time this epidemic is killing tens of thousands of Americans a year, we're seeing the price of naloxone go up by 1000% or more," McCaskill wrote. "Maybe there's a great reason for the price increases, but given the heart-breaking gravity of this epidemic and the need for this drug, I think we have to demand some answers."

How much it costs to save a life

All five pharmaceutical companies that produce naloxone have seen price hikes in recent years or, for the newer entrants such as Adapt, priced their product far above the industry average several years ago.

As of January 2015, Amphastar's version of naloxone was up to $41 a dose, according to Fierce Pharma, a pharmaceutical-industry news site. That follows a price increase from $17 to $33 a dose in October 2014, according to data provided by Truven Health Analytics. In 2001, the price was just $12 a dose.

As of October 2014 — the most recent time for which prices are available — Hospira's version of naloxone was $15.80 a dose. That's up from $0.92 a dose in 2005, according to Truven Health Analytics. The price of Hospira's version of naloxone hit a peak of $21.90 a dose in January 2014. Pfizer purchased Hospira last year.

Meanwhile, Kaléo has raised the price of its naloxone product, Evzio, several times since last year. In November 2015, the price went up to $375, followed by an increase to $1,875 in February 2016. Since then, the price has been raised to $2,250 for each single-dose injector. Evzio, which is an auto-injector that works like an EpiPen and is specifically created for use by people without medical training, was introduced at $287.50 for each single-dose injector in July 2014, according to Truven.

Adapt's Narcan, a nasal-spray form of the drug released in February, costs $63 for each single-dose spray unit, though it does sell the product for approximately half that price to government agencies, community organizations, and patients without insurance, Matt Ruth, Adapt's chief commercial officer, told Business Insider.

Further exacerbating the price problem, according to Bigg, is that most organizations advocate providing overdose victims with multiple doses of naloxone because opioid drugs last longer than naloxone. Such a practice is necessary for safety, but means that these prices only give a partial picture of how difficult it currently is to fund such a program.

The price increases, combined with the increase in demand, have caused sales of naloxone to jump from $21.3 million in 2011 to $81.9 million last year, according to numbers from prescription-tracking company IMS Health and cited by The Los Angeles Times.

Amphastar, one of the two producers of the lower-priced injectable naloxone, saw a revenue increase of 4% in the first quarter of 2016 compared with the first quarter of 2015, according to a press release. The company attributed that increase largely "to an increase in sales of naloxone to $10.3 million from $6.7 million."

All prices stem from purchasing directly from the manufacturer, not the list price, which is higher because of distributor markup. The list price is paid primarily by consumers purchasing naloxone without a prescription.

The source of the increases

According to Bigg, while price increases have been consistent for 20 years, the price hikes jumped in frequency and volume in 2008 after several manufacturers stopped producing the drug, leaving Hospira and Amphastar as the sole manufacturers of naloxone.

Only Mylan, Amphastar, and Hospira, however, make injectable versions — by far the cheapest forms of the drug. Adapt and Kaléo make the more expensive nasal spray and auto-injector, respectively.

Bigg says the limited number of producers has kept the price high and increasing.

But some think the price hikes are a response to a big uptick in demand and point to new laws and programs designed to equip police officers and first responders with naloxone, as well as increase access for the general public.

"Naloxone used to be an item purchased by emergency rooms and ambulances ... Now that harm-reduction organizations have pushed for laws requiring everyone to carry it, the demand has gone up exponentially," Tessie Castillo, the advocacy and communication coordinator at the North Carolina Harm Reduction Coalition, told Business Insider. Pharmaceutical companies "know that they can make more money because of the demand, so they try to."

Over the last couple of years, more than 30 states have acted to increase naloxone access, prescriptions, and use. In 2014, then US Attorney General Eric Holder urged federal law-enforcement agencies to train and equip personnel with naloxone. Such laws and policies were pushed by organizations like Castillo's.

Daniel Raymond, the policy director of the Harm Reduction Coalition, told Business Insider that his organization has noticed increases in the price of naloxone in recent months, but he said he's skeptical that pharmaceutical companies were "profiteering" off the opioid crisis.

Instead, he attributed the increase to broader dynamics "playing out across the pharmaceutical spectrum."

"If naloxone was the only pharmaceutical product that was seeing price increases, I would be very suspicious," Raymond said. "But because this is playing out across the sector ... it's part of a larger trend that the whole healthcare industry and policymakers are struggling to get a handle on."

A Food and Drug Administration analysis of the naloxone market in 2015 attributed the price increase to a general trend across the pharmaceutical industry for generic injectable medicines.

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FILE PHOTO -- EpiPen auto-injection epinephrine pens manufactured by Mylan NV pharmaceutical company for use by severe allergy sufferers are seen in Washington, U.S. August 24, 2016. REUTERS/Jim Bourg/File Photo

EpiPen auto-injection epinephrine pens manufactured by Mylan NV pharmaceutical company for use by severe allergy sufferers are seen in Washington, U.S. August 24, 2016. REUTERS/Jim Bourg

Boxes of Mylan NV's EpiPen 2-Pak allergy shots sit on display for a photograph at a pharmacy in Princeton, Illinois, U.S., on Friday, Aug. 26, 2016. In response to intense criticism over the past few days, Mylan NV moved Thursday to expand assistance programs that help patients with high out-of-pocket expenses -- but didn't go as far as cutting the treatment's list price. Health insurers and U.S. lawmakers criticized the effort as an attempt to cover a 400 percent price hike that won't make the drug more affordable. Photographer: Daniel Acker/Bloomberg via Getty Images

Mylan NV's logo is displayed on a box of EpiPen 2-Pak allergy shots at a pharmacy in Princeton, Illinois, U.S., on Friday, Aug. 26, 2016. In response to intense criticism over the past few days, Mylan NV moved Thursday to expand assistance programs that help patients with high out-of-pocket expenses -- but didn't go as far as cutting the treatment's list price. Health insurers and U.S. lawmakers criticized the effort as an attempt to cover a 400 percent price hike that won't make the drug more affordable. Photographer: Daniel Acker/Bloomberg via Getty Images

Mylan NV's EpiPen allergy shots sit on display for a photograph in Princeton, Illinois, U.S., on Friday, Aug. 26, 2016. In response to intense criticism over the past few days, Mylan NV moved Thursday to expand assistance programs that help patients with high out-of-pocket expenses -- but didn't go as far as cutting the treatment's list price. Health insurers and U.S. lawmakers criticized the effort as an attempt to cover a 400 percent price hike that won't make the drug more affordable. Photographer: Daniel Acker/Bloomberg via Getty Images

This August 24, 2016 photo taken in Hudson, Wisconsin shows a youngster holding Epipens, that he uses to counteract allergic reactions.
A five-fold price hike for EpiPen, which allergy sufferers use to counteract life-threatening reactions, has made Mylan the newest drugmaker to come under attack in the United States for profiteering. Mylan Pharmaceuticals, which holds a near-monopoly position on the epinephrine injectors used by millions against severe allergic attacks, was assailed by two powerful US senators for pumping up the price over six years from $100 to more than $500. That has rendered EpiPens unaffordable to many sufferers -- who must replace them each year -- and is costing the government huge sums to stock schools with them and fund insurance programs which pay for them, the lawmakers said Monday.
/ AFP / Lucas TRIEB (Photo credit should read LUCAS TRIEB/AFP/Getty Images)

This August 24, 2016 photo taken in Hudson, Wisconsin shows Epipens, used to counteract allergic reactions.
A five-fold price hike for EpiPen, which allergy sufferers use to counteract life-threatening reactions, has made Mylan the newest drugmaker to come under attack in the United States for profiteering. Mylan Pharmaceuticals, which holds a near-monopoly position on the epinephrine injectors used by millions against severe allergic attacks, was assailed by two powerful US senators for pumping up the price over six years from $100 to more than $500. That has rendered EpiPens unaffordable to many sufferers -- who must replace them each year -- and is costing the government huge sums to stock schools with them and fund insurance programs which pay for them, the lawmakers said Monday.
/ AFP / Lucas TRIEB (Photo credit should read LUCAS TRIEB/AFP/Getty Images)

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Big Pharma's response

While a statement from Pfizer, on behalf of Hospira, did not respond directly to questions about recent price increases, the company emphasized that it believes it has priced naloxone "responsibly," taking into consideration both "sensitivity to the need for the product" and "the investments necessary to produce high-quality generic drugs as well as ensure appropriate distribution through licensed medical professionals."

The company further touted its commitment to the naloxone market after other manufacturers ceased production.

Amphastar raised the price of its naloxone product because of rising manufacturing costs and investments made in developing its own intranasal naloxone product, Bill Peters, the company's chief financial officer, told The Los Angeles Times.

Kaléo points to the ease of use of its product, the Evzio auto-injector, as justification for its high price. Evzio's auto-injection system provides "voice and visual instruction" to aid administration in an emergency.

"The price of Evzio is reflective of its innovation, years of extensive research to ensure the device is easy to use and reliable and to ensure the broadest access to this potentially life-saving product," Kaléo spokesman Lora Grassilli said in a statement. She added that Evzio is the first FDA-approved naloxone product specifically created for those without medical training.

Ruth, the chief commercial officer for Adapt, told Business Insider that Adapt researched the market prior to setting the price of its Narcan nasal spray in February, which he says has been "well received so far." Ruth further pointed to Adapt's awareness and access initiatives as reasons for Narcan's higher price point.

"Those initiatives aren't free," Ruth said. "We are looking to do this as efficiently as possible and charge an affordable and responsible rate for patients and organizations alike. We believe we've done that."

Both products are increasingly being pushed as the naloxone product of choice for police officers and the general public alike.

While Bigg and Castillo acknowledged that Evzio and Narcan are easier to use than a syringe and vial, both were skeptical that such advancements in delivery justified their considerably higher price tag.

The Chicago Recovery Alliance staff has been using syringes and vials since its inception, according to Bigg, who said that in 7,500 reports on overdose reversals, they've never had someone tell them that they couldn't or didn't understand how to use the syringe.

"We've had no problems with syringes. The syringes are really self-explanatory," Castillo said.

Amphastar has responded to the criticism over naloxone pricing through "increased discounting and rebates." In an Amphastar press release on 2016's first-quarter financials, the company noted that naloxone pricing was down compared with the previous quarter.

Increasing access to many — but not all

Many large organizations like the Chicago Recovery Alliance and government agencies have been insulated to some extent from the rising prices, thanks to special discounts and donations from naloxone producers as well as grants to pay for such products.

Kaléo, for example, has donated 150,000 Evzio auto-injectors to first-responders, public-health departments, and nonprofits since the product's approval in April 2014.

Bigg and Castillo said that their organizations, which provide naloxone to those in need for free, would not be able to exist without such generosity on the part of pharmaceutical companies. According to Bigg, many police departments have money to pay for naloxone because of asset seizures, which confiscate the alleged proceeds or instruments related to crime. Many federal, state, and local government agencies have also been given grants to pay for naloxone.

While these measures have generally increased the availability of naloxone, Castillo says the result is that those hardest hit by the high prices are smaller harm-reduction organizations or community programs that don't have the clout of larger government agencies or the renown of a large nonprofit like the Harm Reduction Coalition. Castillo says that she has spoken to "lots and lots" of organizations and programs that have closed in recent years or failed to get started because of naloxone's high price tag.

"The companies have been pretty good about providing us with deals and discounts, but that's just to us. That is not a normal experience for most organizations that are trying to buy naloxone," Castillo said.

That system has left organizations like Castillo's at the mercy of pharmaceutical companies' generosity. When a pharmaceutical company changes policy — such as earlier this year when Kaléo suspended its charitable donations for the year because of "overwhelming demand" — it can be devastating.

Many of the companies have programs to ensure either lower prices or no cost for patients. Kaléo has a "patient-assistance program" that provides Evzio to people with commercial insurance at no cost. The program allows uninsured people with financial difficulties to request Evzio at no cost.

Adapt's "public-interest pricing" charges approximately half of its list price to community organizations, police departments, public-health organizations, and those without insurance.

Numerous solutions to the price problem have been suggested. Bigg believes that making naloxone available over the counter, as is now allowed in numerous states, would encourage more manufacturers to enter the marketplace and drive down the price — an effort applauded by many doctors and pharmacists. In addition, he thinks that once the FDA approves more naloxone products currently in development, the price should come down as well.

Castillo called for more consistent and transparent pricing, discounts, and donations for all organizations — government and community — that provide naloxone.

Raymond suggested that one factor unique to naloxone makes it difficult to rein in the price increases.

The primary buyers "are all purchasing individually in small amounts so they don't have the leverage to bargain for discounts," Raymond said. He suggested a solution in the form of a bulk-purchasing program that could aggregate demand and push suppliers to drop their prices.